This application relates to genetically engineered mice which are useful as models for generalized lysosomal storage disorders, and in particular for iduronidase deficiency, and to methods of making and using such genetically engineered mice in the evaluation of the therapies for the treatment of such disorders and for evaluation of systems for tissue specific delivery of the therapeutic agents.
Deficiency of .alpha.-L-iduronidase (IDUA) underlies a group of autosomal recessive lysosomal storage disorders termed mucopolysaccaridosis type I (MPS I). MPS I is considered to be the prototypical MPS disorder and represents the most common MPS subtype, occurring at a frequency of approximately 1/100,000 in most populations. The spectrum of clinical features in MPS I, ranges from severe mental retardation with hepatosplenomegaly, dysostosis multiplex, corneal clouding, cardiac involvement and death in early childhood to milder symptoms consisting of corneal clouding, hearing loss, and mild visceral involvement with normal intelligence and life span. Hurler syndrome (MPS I H) represents the most common and severe manifestation of this enzyme deficiency with Scheie syndrome (MPS I S) representing the more mild form of the disease. Many patients follow an intermediate phenotype between that of Hurler and Scheie syndromes.
MPS I has been described in both a feline and canine model. Haskins et al., Ped. Res. 13: 1294-1297 (1979); Spellacy et al., Proc. Nat'l. Acad. Sci. (USA) 80:6091-6095 (1983). The canine model has been well characterized and has been useful in the study of the role of bone marrow transplantation in MPS I as well as early studies of direct enzyme replacement. These animal studies, as well as the observations of the effect of bone marrow transplantation in humans, indicates that the development of enzyme replacement regimes are likely to lead to advancements in the therapy of MPS disorders. Kakkis et al., Biochem. Mol. Med. 58: 156-167 (1996); Shull et al., Proc. Nat'l Acad. Sci. (USA) 91: 12937-12941 (1994). The high cost of canine and feline animal models combined with their relatively long life span, however, makes them less than ideal for this purpose. Thus, it would be advantageous to have a small animal model for evaluating therapeutics for MPS I. It is an object of the present invention to provide a mouse model for this purpose.